NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Key eligibility criteria included a non-alcoholic fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02443116. FINDINGS: Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content from baseline (relative risk 10·0 [95% CI 2·6-38·7] vs 11·4 [3·0-43·8], respectively; p<0·0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during the study. INTERPRETATION: NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population. FUNDING: NGM Biopharmaceuticals.

Is infliximab safe to use while breastfeeding?

Inflammatory bowel disease (IBD) often affects women around the age of conception and pregnancy. Most drugs used to treat IBD are safe in pregnancy, but physicians must consider the clinical implications of certain treatment regimens in young, fertile females. We report an informative case of a pregnant patient with IBD who underwent treatment with infliximab during her pregnancy and while nursing her infant. Serum and breast milk infliximab levels were monitored throughout this time period. This case report suggests that targeted monoclonal antibodies and other biologic agents can be used with caution in pregnant and breastfeeding patients.

New advances in evaluation and management of patients with polycystic liver disease.

Adult polycystic liver disease (APLD) is an autosomal dominant condition most commonly associated with polycystic kidney disease. However, over the last decade it has come to be recognized that APLD is a genetically heterogeneous disorder involving derangements on at least three different chromosomes. Mutations involving chromosomes 16 and 4 accounting for autosomal dominant polycystic kidney disease (ADPKD) type 1 and type 2 have been well described as have their gene products, polycystin-1 and polycystin-2. These have since been joined by a more recently recognized mutation in the short arm of chromosome 19 thought to be responsible for a much rarer form of autosomal dominant polycystic liver disease without any associated renal involvement. Despite the sometimes impressive physical and radiologic findings, only a minority of patients will progress to advanced liver disease or develop complications as a result of massive hepatomegaly. In these patients, medical management alone has proved ineffectual. Therefore, in the symptomatic APLD patient, surgical therapy remains the mainstay of therapy and includes cyst aspiration and sclerosis, fenestration with and without hepatic resection and orthotopic liver transplantation. The surgical literature on treatment of APLD, to include outcome measurements and complication rates are summarized. Additionally, we review other potential organ involvement and resultant complications.

Safety of band ligator use in the small bowel and the colon.

BACKGROUND: Endoscopic band ligation for bleeding small-bowel vascular lesions has been reported as safe and efficacious based on small case series. There have been several other published case reports of band ligators used for bleeding lesions, usually Dieulafoy's lesions, in the stomach, the proximal small bowel, and the colon. In addition, this method has been used for postpolypectomy bleeding stalks. There has never been a critical look at the anatomic consequences of banding in the thinner sections of bowel. METHOD: The purpose of this study is to define the anatomic and histologic consequences of applying band ligator devices to the small and the large bowel. Fresh surgical specimens, both large and small bowel, that were excised because of neoplastic lesions were transported to our endoscopy unit where one end of the intact bowel was sutured shut. A standard upper endoscope was passed via the open end, and the bowel was closed tightly with rubber band ties. The bowel then was insufflated, and band ligators were applied to unaffected mucosa by using a standard technique. Photodocumentation from inside and outside the bowel was obtained. Some of the band polyps were cut above the band, and some were cut below the band in the fresh state. Some were fixed in formalin and examined microscopically. Histologic sectioning occurred at the level of the bands. RESULTS: The results were striking in that there were large holes (1 cm) in the fresh ileum specimen. There was gross serosal entrapment manifested by visible puckers on the outer surfaces of the specimens, especially in the small bowel and the right colon. The left colon, anatomically thicker, was less affected. The histologic evaluation revealed inclusion by the band ligator of the muscularis propria and serosa on the small bowel, the muscularis propria in the right colon, and the submucosa in the left colon. CONCLUSIONS: Based on these findings, we conclude that band ligator devices are not safe in the small bowel and the right colon but probably are safe in the thicker left colon.